The overall objective of this proposal is to study the alterations of hepatic glucose metabolism in endotoxin shock and to delineate the mechanisms responsible for them. The preliminary work of the principal investigator, using endotoxic shock as an experimental model, raises the possibilities that endotoxin may alter the rate of glycolysis by modulating enzyme activities. Therefore, we will investigate: (1) adaptive alterations in key regulatory enzymes in glycolysis and gluconeogenesis during shock; (2) plausible changes in the levels of metabolites involved in the glycolytic pathway and TCA cycle; (3) alterations in adenylate cyclase system by measuring the activities of adenylate cyclase and phosphodiesterase and levels of cyclic AMP; (4) integrity of membrane marker enzymes such as Na/K-ATPase enzyme system and 5'-nucleotidase; (5) the possible structural and chemical modification of pyruvate kinase and glucose-ATP phosphotransferases; and (6) the role of hormones such as insulin and glucagon in regulation of carbohydrate metabolism. Once the metabolic alterations are characterized and the mechanisms involved are elucidated, attempts will be made to prevent the onset or to delay the progression of cellular deterioration by means of pharmacological or metabolic interventions.